Traumatic brain injury (TBI) has been a major cause of death and threat to optimal brain function throughout the entire history of human existence. Delayed secondary injury processes that could be reversed or prevented are important therapeutic targets for TBI. The focus of this project is on secondary injury processes involving the protein tau. Abnormal aggregations of tau have been detected hours to days after injury in the brains of many TBI patients. Tau may be involved in the early development of dementia similar to Alzheimer's disease, and tau is the hallmark of chronic traumatic encephalopathy seen in boxers, football players, and military personnel with TBIs. Importantly, an up-to-date definition of the spectrum of tau pathology now includes not only tau that is visible under the microscope, but also small clusters of tau called oligomers and aggregated forms of tau that can spread through the brain by triggering additional tau aggregation. However, the mechanisms underlying tau pathologies following TBI are not understood, in large part due to the lack until recently of an appropriate small animal model. To address this, we developed the first transgenic mouse model which recapitulates many aspects of tau pathology following experimental TBI. 1) For our first aim, we now propose to test the hypothesis that tau oligomers and spreading tau aggregation contribute to delayed brain degeneration following TBI. These studies will be performed in collaboration with Dr. Rakez Kayed at the University of Texas, Galveston and Dr. Marc Diamond at Washington University, two researchers working at the cutting edge of tau biology. 2) Intriguingly, treatment with an inhibitor of an enzyme called c-jun N-terminal kinase (JNK) before injury reduced TBI-related tau pathology in the brain. For our second aim, we propose to test whether treatment with a JNK inhibitor at therapeutically realistic times after injury blocks tau pathology and improves outcomes in mice. We will assess both short term and longer-term pathological and behavioral outcomes, including innovative tests of social behavior and mood regulation in mice. 3) There are three types of JNK in the brain called JNK1, JNK2 and JNK3. Mice without JNK1 or JNK2 have problems with immune system function whereas mice without JNK3 are actually protected from other types of brain insults. Our hypothesis is that JNK3 is playing a key role and that JNK3 would make a better and safer target for new therapeutics than nonselective JNK inhibitors. We propose for our third aim to create antisense oligonucleotides specifically targeting each type of JNK. We will treat mice with these antisense oligonucleotides and determine whether this reduces tau pathology and improves outcomes following TBI. These antisense oligonucleotides have the potential to be used in human TBI patients, as there are two antisense therapeutics already approved and approximately 35 more in various stages of human clinical trials. Our collaborators, Dr. T.M. Miller at Washington University and Dr. Eric Swayze of Isis Pharmaceuticals are among the world's experts in antisense treatments. The broad, long term goals are to uncover the mechanisms leading to secondary injury processes involving tau and develop therapeutics to block them, with the hope that this would improve outcomes following TBI. The worldwide interest in athletes and military personnel with tau pathology and chronic traumatic encephalopathy underscores the urgency of this line of investigation.